Biguanide derivatives



Patented Nov. 28, 1950 UNITED STATES PATENT OFFICE 2,531,40 H v BIGUANIDE nEitIvArIvEs Francis Henry Swinden Curd, deceased, late of Blackley, Manchester, England, by Muriel Ruth Curd, executrix, Bramhail, England, andFranois Leslie Rose, Blackley, Manchester, England,

assignors to Imperial Chemical Industries Limited, a corporation of Great Britain No Drawing. Continuationot application Serial No. 755,710, June 19, 1941. This application July 25, 1949, Serial N-T106,748; In 'Great Britain October 8,1945 I v Claims. (01. 2604565) This inventionrelates to new'compounds and more particularly it relates to compounds which are useful as antimalarial agents. The present application is a continuation of application Serial Nc. 755,710, now abandoned, which itself-{is a continuation-in-part of copending applications Serial Nos. 701,094, 718,594, 720,096 and-723,450,

Other and further important objects of a new biguanide derivatives of the general' 'formula 1- wherein Z represents an atom selected from the group consisting of bromineand iodine and X and Y represent atoms or radicals selected from anexces's of the nitrogenous base QH when this a is liquid :under the conditions of-reaction employed.

saThenitrogenous compound QI-I may be used eitherin the form of the free base or in the form of a: saltfor example the hydrochloride. ther' the reaction may advantageously be carried outxin the presence of a metal such as zinc or copper which may be used as such or in the form of an oxide, hydroxide orsalt or as a pre-formed addition compound with the amine. There may be used for instance copper powder, hydrated copper oxide, copper sulphate or zinc chloride. In such cases the presence of the metal increases the speed of the reaction and improvesthe yield of the biguanide. Also the biguanide can frequently be conveniently isolated directly from-the reaction mixture in the form of a sparingly soluble complex with the metal salt.

.The. biguanidederivatives of the present invention may also be made by the process described in co-pending application Serial No.

the group consisting of hydrogen, halogen and example by the method described in U. S. Patent No. 2,467,371, viz., by causing a substituted aryldicyandiamide ofthe formula:

Nat xNuou Y 1 NH wherein X, Y, Z and R have the significance in'dicated aboVe, to react with -anitrogenous base of the formula QH, wherein Q has 'the-si'g-' nificance given above. The reaction may conveniently bebrought about by heating the reagents together, if desired in presence of'a solvent or diluent which for convenience may be H hydroxylic solvent for example fl-ethoxyethanol.

701,094 viz., by causing a substituted dicyandiamide of the formula wherein Q has the significance given above to react with an arylamine of the formula s H X I NRH Y I 2 H wherein X, Y, Z and R have the significance given above. This reaction may conveniently be brought about by heating the substituted dicyandiamide with a salt, for example the hydrochloride of the arylamine in presence of a solvent, conveniently for example water or other Again the biguanide derivatives of the present invention may be made by the processes described in copending application No. 718,594, viz. by inter-action of a g'uanidine derivative of the formula:

Fur-

wherein X, Y, Z and R. have the significance given above, with a cyanamide derivative of the formula: Q-CN, wherein Q has the significance stated above, or by interaction of a guanidine derivative, of, the form la;

Qr z-NH:

wherein Q has the significance stated above, with a cyanamide derivative of the formula;

wherein X, Y, Z and R have. the significance, stated above.

These reactions may conveniently be.- effected, by heating the reagents together, optionally in the presence of a solvent or diluent. The guani dine derivative may be used in the form of the free base or, if desired, as a salt such as the hydrochloride, carbonate or sulphate. Where. the

cyanamide is mono-substituted (and; hence acidic,

in nature) it may, if desired, be used in the tom), 0? asalt with a base, the guanidine derivative being then used also in the formv of a salt.

Alternatively the new big-uanide derivatives. of the present invention may be made. by.- the. proc-., esses described in copending application Serial No. 120,096 viz. firstly by: interaction ofan S, substituted guanylisothiourea of the formula:

wherein X, Y, Z and-R have/the significance; given above, with. an amine: of the formula QH, wheree, in Q has the significance given above, or by interaction of the same amine, QH; with aguanylthi'ourea of the formula:

wherein X, Y'; Z and B- have the significancegiven above, in presence oi a desulphurisingagent suchv as the oxides and salts of the heavy metals, particularly those of lead, copper, silver and mercury; or, secondly, by. interaction of an S-substituted guanylisothiourea of the formula:

whereinQ has thesignificance stated; above,, with: n: amine. of the formul whe e n a d R here the si n ficance. stated above, or by interaction of the same; amine:

NRR

with a guanylthiourea of the formula:

QC--NH-C=B H NH:

wherein Q has the significance stated above, in

the presence of a, desulphurising agent,

Or again a guanylthiourea of' the formula:

may be reacted. with ammonia in presence of a desulphurising agent, or, yet again, a guanylthiourea of the formula:

U H I Y may be reacted with ammonia in the presence of a desulphurising agent.

. Ihereaction.in these-processesmay be brought ebQu y-heet ne; therease t g h r. C ve e .ien this. may; be carried out, in presence of a.

olv nt or. di ue ad tag o s y a ydroxyl c or anic..- solven r examp e, hano eth g-etbe ez henq A t rnat ely n e cess of the amino;- c mmuni, whe that s. l quid, y be used as the solvent or diluent, Iheguanylhiou ea. r t e, co r pend ne; sea ky gna y aisothi urz m y be u d, s: suchor it, ma b us d. i t e fo m of sa t or e amp e.- the. y-- *dmthlo iden. he latt r event he; t e. thine te may be l berated in itu by he d itio of. as basifying agent, an equivalent amounfcofi tor eisame od um e hoxide; or sodium m tbox d Aga n he iyine agent may, it d s red, be mer ly n' ex s or he ammompound.

'1 By yet a further alternative the new biguanides of the present invention may be made by the processes described in conending' application Serial No. 723,450, viz, firstly by interaction of a guanidine derivative-of the iormula:

wherein. X, and: B h ve, e i n c stated above, either; with an. S-substit-uted. is0-.

:. h q t e of; e o m la;

herein. Q: has; he gn fica ce s te above. either w th. an S-substituted; i othionr a. of, he aming:

Mltyl s oni NHa I Y wherein X, Y, Z and R have the significance stated above, and a desulphurising agent.

These processes may be brought about by'heating the reagents together. Conveniently this is carried out in presence of a solvent or diluent, advantageously a hydroxylic organic solvent for example methanol, ethanol or p-ethoxyethanol. The thiourea, or the corresponding S-alkylisothiourea, may be used as such as it may be used in the form of its salts, for example the hydrochloride. In the latter event the free thiourea may be liberated in situ by the addition of, as basifying agent, an equivalent amount of, for example, sodium ethoxide or sodium methoxide.

The novel compoundsof this invention are all characterised by a common structure, as expressed by the above general formula, and by substantially common physical and. chemical characteristics. Outstanding among their properties is the pharmaceutical property of bein excellent antimalarial agents; Our novel compounds thus constitute synthetic substitutes for quinine. While the degree of eificacy as anantimalarial agent will, of course, vary from one individual compound to the next, we have tested so large a number of members of the general class against avian. malaria that it may safely be postulated that all the compounds of the class N -p-bromophenyl N -ethy1biguanide BIONHCNHCNHEL lW-p-bromophenyl-M-n-propylbiguanide N -p-bromophenyl-N -n-butylbiguanide N -p-bromophenyl-N -sec.butylbiguanide N-p-bromophenyl-N -dlethylbiguanide N -p-bromophenyl-N -methyl-N' -n-prcpylbiguanide N -p-bromopheny1-N -methyl-N -n-butylbiguanide N -m-iodophenyl-Ndsopropylbiguanide N -p-idophenyl-N -isopropylbiguanide N -piodophenyl-N -n-propylbiguanide N -p-iod0phenyl-N -ethy1bi guanide N p-1odopheny1-N -n-buty1biguanide N -p-iodophenyl-N -methyl-N -1sopropylbiguanide N p-iodophenyl-N-methyl-N -n-propylbiguanide N -3 :4-dibromophenyl-N -isopropylbiguanide Br N 3-bromo-4-chlor0phenyl-N -isopropylbiguanide N-3-bromo-4-chlorophenyl-N -ethylb1guamde N -3-bromo41:hlorophenyl-N -methyl-N -isopropylbiguanide N-3-bromo4- 0dophenyl-N -isopropylbiguanide N-3-bromo4-10dophenyl-N -methyl-N-isopropylbiguanide NE'ICNHCN/ the salt is sparingly soluble.

1?;3-10110ei-chlorophenyl-N -isoprcpylbiguanlde Br-O-NHoNHoNHPra tin its c Other specific compound of this invention: include: 4

- N -m-bromophenyl-N -methyl-N -isopropylbiguanide N -m-br0mophenyl-N-methyllP-n-propylbiguanide N -m-iodophenyl-N-methyl-N -1sopropylb1guanide N-m-iodophenyl-N -methyl-N n propylbiguan1de -3; -dibromophenyl-N -ethylbiguanide N -3 :4-dibromophenyl-N-methyl-N -n;propylbiguanide N -3-brom0-4-iodophenyl-N -methyl-N-n-propylbiguanide N -3-i0d0-4-brcmophenyI-N -methyI-N -isopropylbiguamde N -3-iodo-4-bromophenyl-N -n-propylbiguanide N 3 :4-diiodophenyl-N-etl1ylbiguanide N '4 iiodopheuyl-N -methyl-N -n-propy1b1guanide' N -3 iiodophenyl-N -n-propylbiguanlde N -3 ichlor04-bromophenyl-N -ethylbiguanide N -3 ichloro-4-bromophenyl-N -n-propylbiguanide N -3 -dichloro-4-hromophenyl N methyl N isopropylbiguanide N -3 zfi-dichloro i-bromophenyl N methyl N n propylbiguamie N -4-1odo rmethylphenyl-N -isopropylblguamde N 4-iodo- 3-methy1phenyl-N -n-propylbiguanide N -l-iodo-tt-methylphenyl-N -ethylb1guanide N -4-10do-3-methylphenyl-N -methyl-N -isopropylbiguanide N -4-iodo-3-methylphenyl-N -methyl-N -n-propylbiguanide N 4-bromo-3-methylphenyl-N -isopropylbiguanide N -4-brom0-3-methylphenyl-N-etl1ylbiguanide N -4-bromo-3-methylphenyl-N-n-propylbiguanide N b- 4 briono 3 methylphenyl N methy1-N -isopr0py1- iguan e N -4-bromo-3-methylphenyl-l l-methyl-N -n-propylbiguanide N -3-1odo-1-methylphenyl-Nhsopropylbig'uanide N -3-iodo-4-methylphenyl-N -n-propylb1guanide N -3-iodo4-methylphenyl-N -ethylb1guan1de N -3-i0d0-4methylpheny1-N -methy1-N -i0dophenylbiguanide N -3-iodo-4-methylphenyl-N -methyl-N -n-propylbiguanide N -3-bromo-4-methylphenyl-N-isopropylb1guanide N -3-bromo-4-methylphenyl-N -ethylbiguanide N -3-bromo-4-methylphenyl-N -n-propylbiguamde -bl0 I5lO 4 methylphenyl N methyl N isopropyliguam e N -3-bromo4-methylphenyl-N -111ethyl-N -n-propylbiguanide N -3-bromophenyl-N -methyl-N-1sopropylbiguanide N -3-i0dophenyhNl-methyl-N isopropylbiguanide N-3-1od0-4-chlorophenyl-N -methyl-N -isopropylbiguanide N 3 bromo 4 methylphenyl N methyl -N -1s0propy1- biguanide N4-1odo-3-methylphenyl-N-methyl-N -isopropylbiguanide All these substances may be made by one or more of the methods hereinbefore set forth.

The new compounds are strong bases; they form stable salts with organic and inorganic acids which in many cases are freely soluble in water. The salts may be made by treatin the biguanide in water with the appropriate acid and then removing the water, butthey are more conveniently obtained in a dry form by mixing the components together in an organic solvent such as for example acetone, or an alcohol, in which For use chemotherapeutically it is frequently an advantage to apply the new compounds in the form-of their salts, especially those salts which are water-sole uble. For this purpose there may be used for example the acetates, propionates, butyrates, crononates, formates, malonates, succinates, glycollates, tartrates, nitrates, hydrochlorides, nitrates, sulphates, lactates, methanesulphobis-fi-hydroxynapthoates, or the glycine salts, but it will be understood that many other salts may equally be used, it being understood that for use in the treatment of human malaria it is not desirable to use the salt of an acid which, of itself, possesses toxic properties.

The following examples illustrate but do not limit the invention. The parts are by weight.

. Example 1 V 3.66 parts of n-propylamihe hydrochloride, 7.2 parts of. m-iodophenyldicyandiamide and 215 parts of nitroben'z'e'ne are heated together at 135 C. for 16- hours. On cooling the semi-solid mass obtained is digested with 7% hydrochloric acid and ether, the mixture filtered and the two layers in the filtrate separated. The acid aqueous solution is made slightly alkaline with ammonia and the solid precipitated is filtered off, washed with acetone and crystallised from water. N -miodophenyl-N -n-propylbiguanide hydrochloride, M. P. 208-209 C. is thus obtained as colourless prisms. I

By working in the manner described in Example 1 using other appropriate intermediates, there are obtained the following further b'iguanides.

Example 2 N -4-chloro-3 bromo'phenyl n propylbiguanide hydrochloride of M. P. 197498 G.

Example 3 N -p-iodophen l N isobutylbigu'ariide hydrcchloride of M. P. 231-231 .5 C.

Example 4 N -3-bromo- 4 iodophenyl n --propy-l biguanide hydro-chloride of M. P'. 227*228" C.

Example 5' N' -s-bromo 4 iodophenyl N ethylbiguanide hydrochlorideof P. 220-221 Example 6 I N -3z-dibromophenyl-N n propylbi'guanide hydrochloride 'of P. 2175 -218 G.

' Example 7 Example 9 N -4chlor0-3 -bromophenyl-N -ethylbiguanide hydrochloride of M. P.215-2l6 0.

Example 10 hydrochloride ofMrP. 200---1 G.

k Example 11 'N 4-chioro 3 5 iodophenyl N5 n propylbiguanide hydrochloride of M. P. 198L199 0.

Example 12- n propy-lbig'uan'ide hydrochloride of P. 32 5 c;-..;

Example 13 N -3z4-dibromophenyl 5 N methyl N isopropylbiguanide hydrochloride of M. P. 234- Example 14 N 4 7 chloro 3-bromophenyl-N -methyl l lisopropylbiguanide hydrochloride of M. P. 240- 241" C.

Example 15 N -p-bromophenyl- N' methyl W nropylbi'guanide hydrochloride of M. P. 237 C.

Example 16 N -3-chlor0-4-iodophenyl N methyl-N -hpropylbiguanide hydrochloride of M. P. 229- 230 0.

Example 17 N -3 4 diiodophenyl--N -methyl--N -isopropyl biguanide hydrochloride of M. P. 235 C.

Example 18 N 4 bromo-3--iodophenyl-N -methyl-N -iso gropylbiguanide hydrochloride of M. P. 241*242" Example 19 N 4 bromo-3-iodophenyl N -meth'yl-N -npropylbiguanide hydrochloride of M. P. 208-209 C.

Example 20 N p iodophenyl N -methyl=-N -n-prepyll2-i guanide hydrochloride of M. P. 238C.

Example 21 N 4- chloro-3-iodophenyl-N -methyl-N -n propylbiguanide hydrochloride of M. P. 205-4206" C.

Example 22 N 4 chloro-3-iodophenyl-N methylfibl iso propylbiguanide hydrochloride of M. P. 239-240" C.

Example 23 23 parts of p-bro'z'noaniline' are suspended inw-ater and sufiicient hydrochloric acid is added to give a solution just acid to Congo red. This solution is then diluted to 375 parts with water and 12.6 parts of N -isopropyl-dicyandiamide are added. The mixture is refluxed for 3 hours and then allowed to cool. The solid which separates is filtered oil and washed with a little water. Recrystallisation from water after clarification of the solution with decoloursing charcoal gives a product which has a brownish tinge and a faint odour of p-bromoaniline. It is suspended in a little dry acetone, stirredfo 10 minutes, then-filtered and washed with a little acetone. ther recrystallisation from water gives 'pu'r'e N -'p,-' bromophenyl-N isopropylbiguanide hydrochlo ride which melts at 246 C.

Example 24 A mixture of 12.6 parts of N -isopropyldicyandiamide, 24.3 parts of 3-chloro-4-bromoaniline hydrochloride and parts of- B-ethoxyethanol is heated under reflux for 3 hours. It is then allowed to cool and the crystals which separate are fiItered' or: and washed with a littlep ethoxy ethanol. A further crop of crystals is obtained by the addition of 3 volumes of ethyl acetate to the mother liquor. The total material thus obtained is dissolved in hot alcohol, the solution-is A Mr.

, 9 clarifiedby refluxing for 15 minutes with decolourising carbon, then filtered and allowed to cool and crystallise. There is thus obtained N 3 chlro-4-bromophenyl-N -isopropylbiguanide hydrochloride which melts at 226 C.

Example 25 A mixture of 12.6 parts of N -isopropyldicyandiamide, 26 parts of p.-iodoaniline hydrochloride and 100 parts of p-ethoxyethanol is heated under reflux for 3 hours. It is then cooled, 200 parts of ethyl acetate are added and the mixture is allowed to stand for 1 hour. The crystals which separate are filtered off and washed with a. mixture'of B-ethoxyethanol and ethyl acetate. They are then dissolved in hot water, the solution is clarified by refluxing for minutes with decolourising carbon, then filtered and allowed to cool. The crystals which separate are filtered ofi, washed and dried. There is thus obtained N -p-iodophenyl-N -isopropy1biguanid hydrochloride, which melts at 239 C.

Example 26 Example 27 A mixture of 4.1 parts of N -ethyldicyandiamide, 8.0 parts of p-bromoaniline hydrochloride and parts of p-ethoxyethanol is boiled under reflux for 105 minutes. It is then cooled and the crystalline solid is filtered off and dissolved in dilute hydrochloric acid. The solution is filtered, neutralised with ammonia and salted out with common salt. The N -p-bromophenyl-N -ethylbiguanide hydrochloride thereby precipitated is filtered ofi and purified by crystallisation from water. It has M. P. 233-234 C.

By working in a similar manner using appropriate intermediates there may also be made the following substances:

Example 28 I Na-m-bromophenyl-Nw-isopropylbiguanide hydrochloride, M. P. 226 C.

, 7 Example 29 Na-p-bromophenyl-Nw-n-propylbiguani-de hydrochloride which crystallises from water in colourless v plates, M. P. 221-222 C.

, Example 30 Na-pbromophenyl- Nw-methyl NW isopropyl-, biguanide monohydrochloride which crystallises from water in colourless needles, M. P. 251 C.

Example 31 N 3:5-dichloro-4 -bromopheny1-N -isopropylbiguanide hydrochloride, M. P. 2g4-2e5" C.

' N -3 -iodophenyl-N -isopropylbiguanide hydrochloride, M. P. 246 C.

Example 33 N -4-chloro-3-bromophenyl N isopropylbi- .guanide hydrochloride, M. P. 239 C- Example 34 N 4 iodo 3 bromophenyl-N -isopropylbi- 'guanide hydrochloride, M. P. 236 C.

Example 35 N 3:4-dibromophenyl-N -isopropy1biguanide hydrochloride, M. P. 240 C.

Example 36 Example 3'? W43 4-diiodophenyl-N -isopropylbiguanide hydrochloride, M. P. 237 C.

Example 38 Example 39' N -p-br0mophenyl-N -sec.butylbiguanide drochloride, M. P. 255-256 C.

Example 40 N -3-chloro-4-bromophenyl -N -ethylbiguanide hydrochloride, M. P. 217 C.

Example 41 N -3-ch1oro-4- bromophenyl -N -n,-pro"pylbiguanide hydrochloride, M. P. 217 C.

Example 42 N -3-chloro-4- iodophenyl -N -ethylbiguanide hydrochloride, M. P. 226-227" C.

Example 43 N -3-chloro-4- iodophenyl -N -npropy1biguanide hydrochloride, M. P. 225- C. 1

Example 44 V N -m-bromophenyl -N -n-propylbiguanide hy-. drochloride, M. P. 194195 C. v

' Example 45 N -piodophenyl -N ethylbiguanide hydro chloride, M. P. 2323-2 10? C'.

I, Example 46 N -piodophenyl -N -n-propylbiguanide hydro= chloride, M. P. 222-224 C.

Example 4 N -p iodophenyl N n-buty1biguanide' hydrochloride, M. P. 207 C. 1 I Example 48.

. N -4- chloro -3-iodophenyl -N -ethylbiguanide hydrochloride, M. 1 197-198? c. I Example 49 N -3- chloro -4-bromophnyl-N -methy1-N -npropylbiguanidehydrochloride, M. P." 234 L. "f

7 Example 50'. j

N Q-3- chloro- -4 brom ophenyl --N -met y1-N isopropylbiguanide hydrochloride, M. P. 24? ,C.;

assures Example, 51

n -schloro -4-iodophenyl-N -methyl-N5-is0- 'propylbiguanide' hydrochloride, M; 1?; 231 C.

Example 52 To a solution of 8.7 parts of N-n-butylguanylthiourea ('M. P; 144-5 made by'interaction of N-n-butyldicyandiamide and hydrogen sulphide in 40 parts of acetone at 50 (2., there are added 8 parts of methyliodide. The mixture is then allowed to stand for 2 hours and is then evaporated to dryness under diminished pressure. The residue is dissolved in. parts. of water, 8 parts of bromoaniline added, andv the mixture is boiled gently under reflux condenser for 22 hours. The solution is then made just alkaline to Brilliant Yellow with ammonia and unreacted p-bromoaniline is removed by distillation in steam. To the residual solution. 50 parts of water are added and it is then made acid to Congo red by addition of hydrochloric acid. It is then cooled and filtered andthe filtrate. is added to an excess-oi caustic soda and the mixture. is then extracted with 50 parts of benzene. The benzene solution is washed with water, thenshaken with 75 parts of 7% hydrochloric acid at -40" C. The aqueous layer is then separated and treated with ammonia until the solution is just alkaline to Brilliant Yellow. The precipitated solid is filtered off,

washed with water, redissolved in 2% hydrochloric acid and reprecipitated by addition of ammonia. The last procedure is repeated and the solid is then crystallised twice from water. There is obtained. N -p-bromophenyl N -n-butylbiguanide hydrochloride which has M". P.'2 15 C;

Example- 53 10 .6 parts of p-bromophenylguanidine hydrate and 25 parts of pentanol are mixed, heated to the boil and 15 parts of pentanol distilled from the mixture. 3.9 parts of diethylcyanamide are then added tothe dry pentanol solution of the guanidinc and the mixture is boiled underreflux for 2.5 hours. The reaction mixture. is cooled and diluted with parts of benzene and the whole is ex- Example 54 N -p-bromophenyl-N -isobutylbiguanide; its

monohydroohloride crystallises from water in colourless plates, M. P. 237-238 C.

Example 55 N pbromophenyl -N methyl -N -n-butylbiguamde; 1t crystallises from petroleum ether in colourless plates, M. P. 123-124" C.

Example 56 N -pbromophenyl -N -dimethylbiguanide; it crystallises from ethanol in colourless needles, M. P. -1'76 C.

Emma- 57.

N -p-bromophenylN -cyclohexylbiguanidef it crystallises from benzene in colourless plates, M. P. 181-182 0.; its monohydrochloride crystallises 1mm; wateri-n'colourl'ess needles, M. P. 252- till While it will be understood that medical utility in the treatment of human malaria may formally be. assessed only after extensive clinical. trials, it has been found that. in. this class of compounds the eflicacy of a substance in avian malaria,, par ticularly in Plasmodium gallinaceum infection of chicks, is a good indication of its utility in the treatment, of human malaria. Moreover eflicacy against exoerythrocytic forms of avian malaria organisms in this class of compounds is generally indicative of utility as a causal prophylactic in human malaria. Utility as a causal prophylactic is a very desirable feature of an antimalarial agent and this feature is not possessed by quinine. Quinine is merely curative and, to a degree, clinically prophylactic, these properties being generally indicated by efficacy against the erythrocytic forms in avian malaria. Thus, the compounds of the present invention possess a very important advantage in comparison with quinine. Yet a 'further advantage presented especially by some of the compounds of the present invention is that we have found that they are effective at a dosage which is much smaller in relation to the toxic dose than is the case with manypro-existing antimalarial agents.

Moreover, as: indicated above. the compounds of the present invention are readily made by a number of relatively simple. chemical processes and from. cheap, or potentially cheap, starting materials. For this they show a. clear advantage over already-known synthetic antimalarial agents, notably over: Mepacrine which is 2-chloro- 3--(o diethylaminowmethylbutylamino) 7- methoxyacridine. "Also; being colourless,v they do not possess the undesirable property of staining the skin of the patient.

1. A compound selected from th groupconsisting of the free base form and salts of the biguanides of the general formula:

wherein R. is a lower alkyl radical. 3. A compound of the formula I Br Nn-c-mn-o-Nmz' l l.. in

wherein R is a lower alkyl radical.

4. A'cpmpound of the formula:

13 wherein R is a lower alkyl radical and Z is a radical of a halogen atom of atomic weight greater than chlorine.

5. A compound of the formula:

14 10. N 3:4 dibromophenyl -N isopropylbiguanide.

MURIEL RUTH CURD. Sole emecutria: of the late Francis Henry Swinden Curd.

FRANCIS LESLIE ROSE.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,455,896 Nagy Dec. 7, 1948 2,467,371 Curd et a1 Apr. 19, 1949 2,475,081 Curd et a1 July 5, 1949 OTHER REFERENCES Official Gazette, U. S. Patent Oflice, June 21, 1949, p. 878. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE FREE BASE FORM AND SALTS OF THE BIGUANIDES OF THE GENERAL FORMULA: 